1. FIELD OF THE INVENTION
This invention relates to a process for preparing 2-thioadenosine which is an intermediate for the preparation of S-substituted-2-thioadenosines, useful as a platelet aggregation inhibitor and a coronary vasodilator,
2. DESCRIPTION OF THE PRIOR ART
It is well known that S-substituted-2-thioadenosines possess excellent pharmacological activities. Above all, a certain type of S-substituted-2-thioadenosines is known to have a coronary vasodilating activity as reported in M. H. Maguire et al., J. Med. Chem., 14, 415 (1971); J. A. Angus et al., Brit. J. Pharmacol., 41, 592 (1971); R. Einstein et al., Europ. J. Pharmacol., 19, 246 (1972); and L. B. Cobbin et al., Brit. J. Pharmacol., 50, 25 (1974) and a platelet aggregation inhibitory activity as reported in G. V. R. Born et al., Nature, 205, 678 (1965); F. Michal et al., Nature, 222, 1073 (1969); M. A. Packham et al., Amer. J. Physiol., 223, 419 (1972); and K. Kikugawa et al., J. Med. Chem., 16, 1381 and 1389 (1973). It is also known that 2-thioadenosine is an advantageous intermediate for producing these useful S-substituted-2-thioadenosines as disclosed in K. Kikugawa et al., J. Med. Chem., 16, 1381 (1973).
The conventionally known processes for preparing the above 2-thioadenosine include two methods. One method comprises reacting 2-chloroadenosine which is obtained from naturally occurring guanosine via four steps in a 10% yield with sodium hydrogen sulfide to obtain 2-thioadenosine in a 70% yield (overall yield, 7%) as disclosed by K. Kikugawa et al. in J. Med. Chem., 16 1381 (1973). The other method comprises 3 steps wherein 5-amino-4-cyano-1-.beta.-D-ribofuranosylimidazole (AICN-riboside) is formed from naturally occurring 5-amino-1-.beta.-D-ribofuranosylimidazole-4-carboxamide (AICA-riboside) plus an additional 3 steps herein 2-benzylthioadenosine is obtained in a 20% yield, and then followed by reduction with liquid ammonia-sodium to obtain 2-thioadenosine in a 50% yield (overall yield, 10%) as disclosed by R. Marumoto et al. in Chem. Pharm. Bull. (Japan), 23, 759 (1975). However, both of these conventional methods involve extremely complicated reaction steps as a prerequisite for the production of the desired compound, and are not industrially practical when the resulting 2-thioadenosine is contemplated as a starting material for the production of S-substituted-2-thioadenosines.
Recent investigations have been made on processes for preparing 2-thioadenosine starting with a material that can easily be obtained from natural products in high yield.
The following several processes are known for cyclizing a 5-amino-4-substituted-imidazole ring using carbon disulfide to form a purine ring and incorporating a mercapto group into the 2-position of the purine ring.
5-Amino-1-.beta.-D-ribofuranosylimidazole-4-carboxamide is heated to 180.degree. C with carbon disulfide in methanolic sodium hydroxide to obtain sodium 2-thioinosine (as disclosed in A. Yamazaki et al., J. Org. Chem., 32, 3032 (1967)).
5-Amino-1-cyclopentylimidazole-4-carboxamidine is reacted with carbon disulfide in dimethylformamide containing a suspension of anhydrous potassium carbonate at room temperature to obtain 9-cyclopentyl-2-thioadenine (as disclosed in J. A. Montgomery and H. J. Thomas, J. Med. Chem., 15, 182 (1972)).
5-Amino-4-cyano-1-.beta.-D-ribofuranosylimidazole is reacted with carbon disulfide in pyridine to obtain 2,6-dithio-9-.beta.-D-ribofuranosylpurine (as disclosed in R. Marumoto et al., Chem. Pharm. Bull. (Japan), 23, 759 (1975)).
4-Aminoimidazole-5-carboxamide oxime is reacted with carbon disulfide in pyridine and methanol at room temperature to obtain 2-thioadenine 1-N-oxide (as disclosed in R. M. Cresswell and G. B. Brown, J. Org. Chem., 28, 2560 (1962)).
All these conventional processes comprise cyclization of a 4-carboxamide, 4-cyano, 4-carboxamidine or 4-carboxamide oxime type 5-aminoimidazole, in which a purine ring having a mercapto group introduced into the 2-position thereof can be formed simply by effecting a ring-closure using carbon disulfide.
Instead of the carbon disulfide employed above, 5-amino-1-.beta.-D-ribofuranosylimidazole-4-carboxamidine is reacted with 1,1'-thiocarbonyldiimidazole in dimethyl sulfoxide to obtain 5-amino-1-.beta.-D-ribofuranosylimidazole-4-carboxamidine cyclic 3',5'-phosphate (as disclosed in Japanese Patent Application Laid Open to Public Inspection No. 109395/1974 published on Oct. 17, 1974 (corresponding to U.S. Patent Application Serial No. 330,306 filed Feb. 7, 1973) and R. B. Meyer et al., J. Amer. Chem. Soc., 96, 4962 (1974)). However, this process is disadvantageous in that the reagent, 1,1'-thiocarbonyldiimidazole, is too expensive to use in industrial production, and the product can only be obtained in a yield of as low as 48%.
Further, when a 4-carboxamide or 4-cyano type 5-amino-imidazole is cyclized with carbon disulfide for the purpose of preparing 2-thioadenosine, a number of subsequent working-up steps from 2-thioinosine to 2-thioadenosine are required until the final product can be obtained as reported, e.g., in R. Marumoto et al., Chem. Pharm. Bull. (Japan), 23, 759 (1975). The purpose may be accomplished by reacting a 4-carboxamidine type 5-aminoimidazole with carbon disulfide. However, as shown in the above cited references [J. Med. Chem., 15, 182 (1974) and J. Amer. Chem. Soc., 96, 4962 (1974)], the starting material can first be obtained through 4 required reaction steps starting from adenosine and, consequently, the total yield of this process is low.
4-Carboxamide oximes or the O-substituted derivatives thereof which are used as a starting material for the production of the 4-carboxamidine type 5-aminoimidazoles can be obtained starting with adenosine via 2 to 3 reaction steps with a high yield. However, when the cyclization of the resulting 5-amino-imidazoles is effected with carbon disulfide, these starting oximes remain in the reaction product as an N-oxide or an O-substituted-N-oxide of 2-thioadenosine. Removal of the resulting N-oxides or O-substituted-N-oxide group can generally be carried out by reduction, but the procedures involved therein are not always easy. For example, only one instance of reduction in a purine ring N-oxide is reported in T. Fujii and T. Itaya, Tetrahedron, 27, 351 (1971). Furthermore, the fact that the purine ring has a mercapto group in the 2-position would make it difficult to carry out a selective oxidation of the N-oxide, which, in fact, has never been attempted in the art.